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Expansion by Self Antigen Is Necessary for the Induction of Experimental Autoimmune Encephalomyelitis by T Cells Primed with a Cross-Reactive Environmental Antigen¹

Ana M. Carrizosa^*, Lindsay B. Nicholson^*, Michael Farzan, Scott Southwood, Alessandro Sette, Raymond A. Sobel^§ and Vijay K. Kuchroo^2,*

^* Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; Division of Human Retrovirology, Dana Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115; Epimmune, San Diego, CA 92121; ^§ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, and Veteran’s Administration Medical Center, Palo Alto, CA 94304.

Cross-reactivity with environmental antigens has been postulated as a mechanism responsible for the induction of autoimmune disease. Experimental autoimmune encephalomyelitis is a T cell-mediated autoimmune disease model inducible in susceptible strains of laboratory animals by immunization with protein constituents of myelin. We used myelin proteolipid protein (PLP) peptide 139–151 and its analogues to define motifs to search a protein database for structural homologues of PLP_139–151 and identified five peptides derived from microbial Ags that elicit immune responses that cross-react with this self peptide. Exposure of naive SJL mice to the cross-reactive environmental peptides alone was insufficient to induce autoimmune disease even when animals were treated with Ag-nonspecific stimuli (superantigen or LPS). However, immunization of SJL mice with suboptimal doses of PLP_139–151 after priming with cross-reactive environmental peptides consistently induced experimental autoimmune encephalomyelitis. Furthermore, T cell lines from mice immunized with cross-reactive environmental peptides and restimulated in vitro with PLP_139–151 could induce disease upon transfer into naive recipients. These data suggest that expansion by self Ag is required to break the threshold to autoimmune disease in animals primed with cross-reactive peptides.

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